HIV infection of the nervous system results in chronic infection, inflammation and cognitive decline in many patients with no effective treatments. Inflammation appears early in the disease process and causes progressive neural damage due, in part, to factors released by activated microglia and macrophages. In cultured neurons these factors induce intracellular calcium accumulation, cytoskeletal damage and focal swelling, much like the early Alzheimer disease (AD)pathology, suggesting a common substrate for disease progression. In gp120 transgenic mice and AD mouse models we recently identified a unique form of Tau that accumulated in the neuritic swellings. The same Tau accumulated naturally in the hippocampus of aging and gp120 Tg mice in parallel with p75NTR expression and Iba-1 immunoreactive microglia suggesting an important link between inflammation, aging and neurodegeneration. In preliminary multielectrode array (MEA) studies, these early indices of neural damage and Tau accumulation correlated with the appearance of burst-like activity patterns, increased spike frequencies and a decreased density of neuron interconnections, all signs of network dysfunction. At the cellular level, hyperresponsiveness contrasted with the restricted network activity highlighting the need to better understand how changes in neuronal function translate to network function. Treatment strategies targeted to these early, reversible manifestations of the disease process have the potential to stabilize cognitive function and perhaps suppress pathogenesis. We propose a series of experiments that will provide complementary in vitro and in vivo analyses of the temporal development of network dysfunction in mouse models of HIV-associated inflammation. In vitro studies of mixed neural cultures from gp120 Tg, Tau overexpressing, p75 neurotrophin receptor deficient and wild type mice will utilize high content recording of neural activity on 4096 electrode culture grids, calcium imaging of primary neurons, morphometry and immunocytochemistry to examine the contribution of HIV pathology to the development of neural and network dysfunction under both normal and disease prone conditions. Parallel studies will examine the relative contribution of microglia as well as HIV Tat protein. Subsequent microwire array recording in vivo to examine hippocampal mesoscale neural network activity, communication and function in gp120 Tg mice crossed to Tau overexpressing and p75 deficient mice will begin to reveal how network behavior is modified as pathology progresses. Mice with confirmed network dysfunction will be evaluated for cognitive function which will be correlated with MRI/PET studies of synaptic loss and microglial activation with the SV2A synaptic vesicle protein probe 11C-UCB-J and the mitochondrial TSPO probe 18F-PBR111, respectively. We believe this integrated approach will identify and characterize HIV-associated network dysfunction and open new avenues for disease modifying therapeutic intervention.